Nicholas R. De Lay, PhD

Education

Postdoctoral Fellow

National Institutes of Health

Ph.D.

University of Illinois at Urbana-Champaign, 2007

Areas of Interest

Research Interests

Molecular mechanisms by which small noncoding RNAs (sRNAs) regulate gene expression. The role of sRNAs in shaping bacterial behavior.

Small noncoding RNAs (sRNAs) that regulate gene expression by base-pairing with target mRNAs are found in all three domains of life.  In many bacterial species including numerous human pathogens, a large class of these sRNAs bind to an RNA chaperone called Hfq. Hfq stabilizes the sRNA and facilitates pairing to a short complementary sequence in a target mRNA. Pairing of the sRNA to the mRNA results in either a decrease in mRNA stability and/or translation (negative regulation) or an increase in mRNA translation (positive regulation). Disrupting sRNA-mediated regulation in bacteria by deleting hfq results in defects in growth and/or virulence and an increased sensitivity to antibiotics. These results suggest that proteins critical for Hfq-dependent sRNA-mediated regulation may be good targets for antibiotics. The identification of new molecular targets of antibiotics is of growing importance given the rising occurrence of multi-drug resistance among gram-negative bacterial pathogens.

One focus of the research in my laboratory is on identifying and characterizing the key proteins involved in sRNA-mediated regulation using E. coli as the model system. This research will lead to a greater understanding of the process of sRNA-mediated regulation and to the identification of novel targets for antibiotics. Using a genetic approach, I have identified and begun to characterize an additional factor required for Hfq-dependent sRNA-mediated regulation called polynucleotide phosphorylase (PNPase). The findings of this work have resulted in a new model for Hfq-dependent sRNA-mediated regulation. In this model, both Hfq and PNPase bind to separate sites on the sRNA, protecting the sRNA from degradation. This complex then facilitates pairing of the sRNA with a target mRNA. Some of the questions raised by this model that we want to address are: How does PNPase block the degradation of sRNAs? What keeps PNPase itself from using its exoribonuclease activity to degrade sRNAs? Does PNPase play additional roles in sRNA-mediated regulation? Are there additional proteins involved in sRNA-mediated regulation and what steps are they involved in?

The second focus of my laboratory is on understanding the role of sRNAs in regulating bacterial behaviors such as motility, biofilm development, and pathogenesis. The species E. coli consists of many different pathogenic strains that cause a variety of diseases in humans ranging from diarrhea to neonatal meningitis to urinary tract infections. Hfq-dependent sRNAs play an important role in the pathogenesis of these E. coli strains. The long term goals of this research are to understand the differences in the repertoire of sRNAs and their targets among these diverse E. coli strains and how this variation contributes to differences in motility, biofilm development, and interactions with hosts.

Publications

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